Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Cornelia de Lange syndrome (CdLS [OMIM #122470]), which was recognized as a distinct entity over 70 years ago, is a clinically heterogeneous developmental disorder characterized by facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities (Brachmann 1916; de Lange 1933). The distinctive facial features include synophrys, long eyelashes, depressed nasal bridge with an up-tilted nasal tip and anteverted nares, thin upper lip with down-turned corners of the mouth, and low-set, posteriorly-rotated ears. Abnormalities in the upper extremities range from subtle changes in the phalanges and metacarpal bones with small hands to oligodactyly and severe reduction defects. Gastrointestinal abnormalities include gastroesophageal reflux, intestinal malrotation, and pyloric stenosis. Additional relatively frequent features include hearing loss, ophthalmologic findings (ptosis, myopia), palatal abnormalities, genitourinary abnormalities (cryptorchidism, hypospadias), cardiac septal defects, and congenital diaphragmatic hernias. Growth retardation is an almost universal finding in CdLS and is typically of prenatal onset. Standard growth curves have been established for height, weight, and head circumference (Kline et al. 1993a). The mental retardation in CdLS is often severe, with a mean I.Q. of 53 (range 30-86) (Kline et al. 1993b). Many patients also demonstrate autistic-like behavior and self-injurious behavior (Jackson et al. 1993).
The clinical features seen in individuals with classic CdLS are striking and easily recognizable; however, there is marked variability and a milder phenotype has been consistently described (Ireland et al. 1993; Saul et al. 1993; Selicorni et al. 1993; Van Allen et al. 1993). Indeed, even the first reported descriptions of CdLS were markedly discrepant in phenotype: Brachmann described major upper limb reduction abnormalities (Brachmann 1916), while de Lange reported no limb reduction defects (de Lange 1933). This phenotypic variability and lack of a diagnostic marker have complicated the diagnosis and counseling for CdLS.
The prevalence of CdLS is estimated to be as high as 1 in 10,000 (Opitz 1985) and most cases appear to be sporadic. Pedigree analyses of several families demonstrate autosomal dominant inheritance with both maternal and paternal transmission (Robinson et al. 1985; Bankier et al. 1986; Halal and Silver 1992; Feingold and Lin 1993; Chodirker and Chudley 1994; Kozma 1996; Russell et al. 2001; McConnell et al. 2003). Assuming autosomal dominant inheritance, cases of apparently unaffected parents having multiple children with CdLS were hypothesized to be the result of germ line mosaicism (Beratis et al. 1971; Lieber et al. 1973; Fryns et al. 1987; Naguib et al. 1987; Krajewska-Walasek et al. 1995; Caksen et al. 2001). This hypothesis of germ line mosaicism was further supported by the identification of several families where an unaffected parent had multiple affected children through different partners (Krantz et al. 2001).
Due to the severity of the physical and cognitive impairment seen in CdLS, it has long been felt that an underlying chromosomal imbalance encompassing multiple genes may be etiologically responsible. Although several chromosomal rearrangements have been reported in the past in patients with CdLS, no consistent abnormalities have been identified (Kousseff et al. 1994). The identification of individuals with CdLS who carry de novo balanced translocations (Ireland et al. 1991) are of interest as they may be involved in disruption of the causative gene. The frequency of balanced translocations in the general population is estimated to be 1/500 (Bugge, M. 2000), so reports of a handful of apparently unrelated de novo translocations in children with CdLS, most of whom will have chromosomal analysis performed, may in fact be incidental.
Partial phenotypic overlap between individuals with CdLS and individuals with duplications of chromosome 3q (dup 3q syndrome) has been noted (Falek et al. 1966; Aqua M.S. et a. 1995; Ireland et al. 1995; Rizzu et al. 1997) and resulted in a locus assignment in OMIM for CdLS at 3q26 (See NCBI website at nlm. nih.gov/htbinpost/Omim/dispmim?122470). The identification of a de novo t(3;17)(q26.3;q23.1) translocation in a patient with a classic CdLS phenotype (Ireland et al. 1991) with the 3q breakpoint within the dup3q critical region further implicated this region. The 3q breakpoint has been cloned and a novel gene identified at the breakpoint however no mutations have been identified in this gene or in neighboring genes in individuals with CdLS (Smith et al. 1999; Tonkin et al., 2001). Linkage analysis to this region did not demonstrate cosegregation of chromosome 3q markers with the CdLS phenotype in all of the families studied (Krantz et al. 2001). These reports suggested that loci other than 3q26-27 may harbor a CdLS disease gene.
In light of all the foregoing, it is clear that a need exists for a new diagnostic marker for CdLS and methods of use thereof. Such a marker and methods can be used to advantage for genetic counseling and prenatal screening.